What is Megace (megestrol acetate)?

What is Megace (Megestrol Acetate)?

Megace (megestrol acetate) is a synthetic progestational hormone primarily used as an appetite stimulant in patients with cancer-related or AIDS-related anorexia-cachexia syndrome, though it carries significant risks including thromboembolic events and increased mortality. 1, 2

Primary Indications

Megestrol acetate has two distinct FDA-approved uses:

• Palliative treatment of advanced breast or endometrial carcinoma (recurrent, inoperable, or metastatic disease), though it should not replace standard treatments like surgery, radiation, or chemotherapy 2
• Treatment of anorexia, cachexia, or unexplained weight loss in patients with AIDS and cancer, where it functions as an appetite stimulant 1, 3

Mechanism of Action

Megestrol acetate stimulates appetite through multiple pathways 4:

• Downregulation of proinflammatory cytokines (such as IL-1, IL-6, TNF-alpha) that contribute to cachexia 4, 5
• Direct influence on the hypothalamic appetite regulation center 4, 5
• Glucocorticoid-like effects at higher doses, which may contribute to its appetite-stimulating properties 4, 5

Clinical Efficacy

The evidence demonstrates modest but significant benefits 1, 3:

• Approximately 1 in 4 patients (25%) experience appetite improvement 1
• Only 1 in 12 patients (8%) achieve measurable weight gain 1
• Patients are 2.57 times more likely to experience appetite improvement compared to placebo 1, 5
• Patients are 1.55 times more likely to gain weight compared to placebo 1

Critical Limitation of Weight Gain

The weight gained is primarily adipose tissue rather than skeletal muscle, which significantly limits the clinical benefit since preservation of lean body mass is more important for functional status and quality of life 1, 4, 5

Dosing Regimens

Standard Dosing for Appetite Stimulation

• Initial dose: 400-800 mg/day orally is recommended by most current guidelines 1
• Alternative starting dose: 160 mg/day can be used with titration upward based on response 1
• Optimal dose range appears to be 480-800 mg/day for maximal appetite stimulation 1, 4
• Doses above 480 mg/day show diminishing additional benefit, though higher doses are associated with greater weight improvement 6, 1

Formulation Considerations

• Liquid suspension is preferred over tablets because it is less expensive and more bioavailable 1
• The concentrated nanocrystal formulation (Megace ES) allows for smaller volume dosing (5 mL vs 20 mL daily) with improved bioavailability 7, 8

Major Risks and Safety Concerns

Thromboembolic Events

• Approximately 1 in 6 patients (17%) will develop thromboembolic phenomena, including deep vein thrombosis and pulmonary embolism 1, 4
• Relative risk of 1.84 compared to placebo (95% CI: 1.07-3.18) 1, 5
• Regular assessment for thromboembolic phenomena is essential throughout treatment 1, 4

Mortality Risk

• 1 in 23 patients will die from treatment-related complications 1
• Relative risk of death is 1.42 compared to placebo 1, 4, 5

Other Common Side Effects

• Edema occurs with relative risk of 1.36 compared to placebo 1, 4
• Adrenal suppression can occur with long-term therapy, requiring monitoring of adrenal function 1, 4, 9
• More than 40 different side effects have been documented in clinical trials 3

Duration of Therapy

Duration should be limited rather than indefinite, with regular reassessment of whether continued therapy is warranted based on response and quality of life goals 1, 5. The optimal duration is not well-established, but benefits must be weighed against risks, particularly for longer-term use 1, 4.

Alternative Options

Corticosteroids

• Dexamethasone 2-8 mg/day provides similar appetite stimulation with a different toxicity profile and significantly lower cost 1, 4, 5
• Corticosteroids have rapid onset of action but should be restricted to 1-3 weeks maximum due to cumulative toxicity including muscle wasting, insulin resistance, and increased infection risk 1
• The choice between megestrol acetate and corticosteroids should consider expected survival and comorbidities 1

Combination Therapy

• Megestrol acetate plus olanzapine 5 mg/day showed superior weight gain in one trial (85% vs 41% achieving ≥5% weight gain) 1, 4, 5
• Combination with exercise programs, particularly resistance training, may help preserve lean body mass 1

Inferior Alternatives

• Cannabinoids (dronabinol) are inferior to megestrol acetate for appetite stimulation in cancer patients 1
• Cyproheptadine lacks sufficient evidence of benefit for cancer cachexia 1

Clinical Context for Use

Megestrol acetate is most appropriate for patients with cancer-related or AIDS-related anorexia/cachexia where increased appetite is an important quality of life goal, particularly when life expectancy is measured in months rather than weeks 1, 5. It should be considered as a first-line pharmacological intervention after or in combination with dietetic and oral nutritional management 6, 1.

Required Monitoring

• Regular assessment for thromboembolic phenomena (leg swelling, chest pain, shortness of breath) 1, 4
• Weight monitoring to assess response 1, 4
• Adrenal function testing in patients on long-term therapy 1, 4